The fundamental goal of this research is to understand the interplay of aging, mechanical regulation of bone mass, and osteoporosis. In osteoporosis, fractures occur because of structural failure during normal mechanical loading, largely due to reduced skeletal mass. This application proposes to study the skeletal biology of mechanical loading because mechanical loading is a powerful regulator of bone mass in vivo. In addition to hormonal, nutritional, and genetic factors, the reduced bone mass in osteoporosis can be related to reduced mechanical loading from decreased physical activity, or to an age- related reduction of the biological response to normal mechanical loading, or a combination. In any case, understanding the mechanism(s) involved in the biological response to mechanical loading will increase the ability to devise lasting cures or preventions for osteoporosis. This project will investigate the biological response to mechanical loading of the skeleton by using an in vivo model of controlled external loading to study age, estrogen deficiency, a common agent for osteoporosis treatment, and autocrine/paracrine mediators as transducers of the loading signal. The hypotheses to be tested are: (1) the age-related decrease in bone response to mechanical stimulation is progressive, (2) bone adaptation to mechanical loads is similar in pattern, but lower in magnitude in estrogen deficient rats than in control rats, (3) bisphosphonates depress the bone response to mechanical loading, (4) prostaglandins mediate the transduction of mechanical signals to bone cell responses, and (5) changes in periosteal mRNA expression after mechanical stimulation are depressed with age. The specific aims are: (1) to compare the bone forming response to similar mechanical loads in four age groups of rats (Fischer 344), (2) to compare the bone forming response in estrogen deplete and control rats at four ages, (3) to test the effect of bisphosphonates, a treatment to prevent estrogen-related bone loss, on the bone forming response to mechanical loading, (4) to test the effect of indomethacin, a prostaglandin inhibitor, on the bone formation response to moderate and high bending forces, and (5) to compare mRNA expression after mechanical loading in four age groups of rats. The methods of assessment include histomorphometry, biomechanics, and mRNA analysis. The results of these studies will lead to an understanding of the aged bone response to mechanical loading and the cascade of signals from mechanical loading to increased bone cell activity. This knowledge will help devise methods of increasing the skeletal response to daily mechanical loading and perhaps maintain bone mass with aging.